SSRI's are widely used for the treatment of various disorders. Major depression is the most common among those disorders treated with an SSRI. Other well-known disorders that can be treated with SSRI's are dysthymia, premenstrual dysphoric disorder, panic disorder, obsessive compulsive disorder, social phobia, post-traumatic stress disorder, generalised anxiety disorder, obesity and alcoholism (Schatzberg J. Clin Psychiatry, 61, Suppl 11: 9-17, 2000; Masand and Gupta, Harvard Rev Psychiatry, 7: 69-84, 1999). Evidence is accumulating that such drugs have also beneficial effects in less common disorders, such as trichotillomania, paraphilia and related disorders and borderline personality disorder. Benefits are also obtained with use of an SSRI in smoking cessation and in the control of addictive behavior.
It occurs regularly that a once started treatment with an SSRI fails to have clear therapeutic results or has to be discontinued due to poor tolerance of side effects. Known side effects of SSRI's are headache, nausea, appetite inhibition, agitation, sleep disturbance, and disturbance of sexual functions, such as anorgasmia and loss of libido. In practice the overall therapeutic result of a regularly applied SSRI treatment is the resultant of the improvement of the disorder and the burden of negative side effects. In view of the existence of alternatives to SSRI's for the treatment of disorders, treatment results can be improved when patients are selected for tolerance and chance of success of an SSRI. Patients at risk for negative side effects can be treated with a treatment other than a treatment with an SSRI. Consequently, it will be very useful if it were possible to predict the occurrence of cumbersome side effects of a treatment with an SSRI.
It is a known assumption that the genetic make-up of a person can contribute to the individually different responses of persons to a medicine (Roses, Nature 405:857-865, 2000). Examples of genetic factors, which determine drug tolerance, are drug allergies and severely reduced metabolism due to genetic absence of suitable enzymes. A case of a lethal lack of metabolism due to cytochrome P-450 2D6 genetic deficiency is reported by Sallee et al J Child & Adolesc. Psychopharmacol, 10: 27-34, 2000. The metabolic enzymes in the liver occur in polymorphic variants, causing some persons to metabolise certain drugs slowly and making them at risk for side effects due to excessively high plasma drug levels. Many genes that are expressed in the brain such as neurotransmitter receptors and transporter proteins have polymorphic variants. These variants may influence the interaction of a drug with cells of the brain, which may influence the frequency of drug side effects (Cravchik and Goldman, Arch Gen Psychiatry 57:1105-1114, 2000). Variants of the gene for the serotonin 2A receptor (5-HT2A receptor) exist, which differ in one nucleotide at location 102. Alleles with 102C and 102T exist. This particular polymorphism has been explored in attempts to find genetic predictors for schizophrenia symptomatology, suicidal ideation, alcohol dependency, bipolar affective disorder, fibromyalgia, Tourette's syndrome, and other diseases. Such attempts have met with little confirmed success thus far (Bondy et al., Am J Med Genetics, 96:831-835, 2000; Massat et al., Am J Med Genetics, 96:136-140, 2000; Serretti et al., Am J Med Genetics, 96; 84-87, 2000; Bondy et al., Neurobiol Diseases, 6:433-439, 1999; Du et al., Am J Med Genetics, 96:56-60, 2000).